Dienic steroids and method of preparing the same



United States Patent 3,118,919 DTENHC STERGID AND METHGD 0F PREPAPTNGTHE SAME John ll. Brown, Pearl River, andSeymour Bernstein, New Qity,N.Y., assignorstoAmerican Cyanamid (Zornpany, Stamford, Conn, acorporation of Maine No Drawing. Filed .iune 15, 1962, Ser. No. 262,7958 Claims. (Cl. 260-39.7.45)

wherein R is hydroxyl and R is selected from the group consisting ofvinyl, chloroethynyl.

The compoundsofthis invention are, in general, White crystalline solids,relatively insoluble in water but soluble in lower alkanols, ethylacetate, acetone, tetrahydrofu-ran, methylene chloride and the like.

The compounds of the present invention are prepared from intermediatesof the formula:

wherein R is selected from the group consisting of hydroxy-l and loweralkanoyl and R is selected from the group consisting of hydrogen,methyl, vinyl and chloroethynyl. The preparation of these intermediatesis described in the chemical literature as indicated hereinafter.

in order to prepare the present compounds, the intermediates are reactedwith an orthoforrnate ester in a solvent at from about to about 50 C.The orthoformate esters can be, for example, methyl orthoformate, ethylorthoferrnate, etc. The solvents can be, for example, lower alkylalcohols such as methanol, ethanol, propancl, etc. Also1,4-dioxane-alcohol solvent mixture can be used as Well as an excess oforthoformic ester. The reaction product is hydrolyzed with a strong acidsuch as, for example, sulfuric, hydrochloric, p-toluenesulfonic,perchloric acids or the like.

The present compounds are preferably recovered from the reaction mixturefollowing hydrolysis by dilution with water and separation of theprecipitate by filtration. T he product is further purified bycrystallization and recrystallization, is desired.

The compounds of the present invention such as 17/3-hydroxy-17m-methyl-19-norandrosta-5 ('10) ,9 l 1) dien- 3-one areanabolic agents and useful in steroid therapy for this purpose. Othershaving the 17u-vinyl, chloroethynyl, etc. groups present are useful asoral progestational agents in the treatment of dysmenorrhea, habitualabortion, menopausal syndrome and the like. The present compounds can beincorporated with fillers, excipients, flavors, etc. and compounded intotablet, capsules, pills and other well known pharmaceutical forms.

The following examples illustrate in detail the preparation ofrepresentative compounds of the present invention.

Example Z.Preparati0n 0f l7fi-Hydr0xy-19-Norandrostad(10),9(11)-Dien-3-One17,8-hydroxy-19-norandrosta-4,9(10)=dien-3-one is prepared by the methoddescribed in J. Am. Chem. Soc., 82, 2402 (19-60). p-Toluenesulfonic acid(100 mg.) is added to a solution of 17B-hydroxy-l9-nonandrosta-4,9-(10)-dien-3-one (200 mg.) in methanol (4 ml.), methylene chloride (4ml.) and methyl orthofor-mate (4 ml). After 10 minutes pyridine (2 ml.)is added followed by methylene chloride. The mixture is Washed withwater and dried and the gumobtained by removal of solvent is dissolvedin petroleum ether and chromatographed on a synthetic magnesium silicate(10 g.). The gum eluted with 1% acetone in petroleum ether is dissolvedin acetone (6 ml.) and dilute sulfuric acid (3 drops; 8% v./v.) isadded. After 5 minutes the solution is diluted with water and themixture is kept in the cold for 1 hour. The material Which has separatedis collected, dried and crystallized from acetone-petroleum ether togive 17fl-hydroxyl9-norandrosta-5 10 ,9 l l -dien-3-one as needles mg.)melting point about l001l8 C.

Example 2.-Preparati0n of 1 7B-Hydroxy-1 7a-Methyl-IQ-NOrandrOsta-SUO),9(11)-Dien-3-One Example 4.Preparati0n of19-N0rpregna-5 (10) ,9(1]

Diene-3,20-Di0ne The product of the example is obtained by treating 19-norpregna-4,9(l0)-diene-3,20-dione [J. Am. Chem. 800., 82, 2402 (1960)]as in Example 1 above.

Example 5.-Preparati0n of 17a-Chl0r0ethynyl-17B-Hydr0xy-19-N0randr0sta-5(10),9(11)-Dien-3-One The product of the exampleis obtained by treating 17achloroethynyl-17B-hydroxy 19 norandrosta4,9(10)- dien-3-one [J. Am. Chem. Soc, 83, 4663 (1961)] as in Example 1above.

We claim: 1. A compound of the formula:

Ln -z i j wherein R is hydroxyl and R is selected from the groupconsisting of vinyl and chloroethynyl.

2. The compound 17,8-hydroxy 17a vinyl "19 norandrosta-5(=10 ,9 l l-dien-3-one.

3. The compound 17a-chloroethynyl-17 {3-hydr0xy-19- norandrosta-S 10) ,91 1)-'dien-3-0ne.

4. A method of preparing compounds of the formula:

wherein R and R are defined as above with an orthoformate ester in asolvent inert to the reactants, subsequently hydrolyzing by the additionof a mineral acid and recovering said compound therefrom.

5. A method of preparing 17B-hydroxy-l9-norandrosta-5(10),9(l1)-dien-3-one which comprises contacting 17B-hydroxy 19norandro'sta-4,9(10)-dien-3-one with a lower alkyl orthoformate in alower alkyl alcohol, subsequently hydrolyzing the reaction product witha mineral acid and recovering said product therefrom.

6. A method of preparing l7fi hydroXy-l7at-mcthyl-l9- n0randrosta5(10),9(11) dien 3 one which comprises contacting 17fi-hydroxy 17m methyll9 norandrosta- 4,9(l0)-dien-3-one with a lower alkyl orthoformatc in alower alkyl alcohol, subsequently hydrolyzing the reaction product witha mineral acid and recovering said product therefrom.

7. A method of preparing 17B-hydroxy-l7a-viny1-19- norandrosta-Sl0),9(11) dien 3 one which comprises contacting 17B hydroxy 17ozvinyl-19-norandrosta-4,9 (l0)-dien-3-one with a lower alkyl oithoformatcin a lower alkyl alcohol, subsequently hydrolyzing the reaction productwith a mineral acid and recovering said product therefrom.

8. A method of preparing17a-chloroethynyl-17fl-hydroxy-l9-norandrosta-5(l0),9(l1)-dien 3 onewhich comprises contacting l7a-chloroethynyl-l7 3-hydroxy-l9-norandrosta-4,9(10)-dien-3-one with a lower alkyl orthoforrnate in alower alkyl alcohol, subsequently hydrolyzing the reaction product witha mineral acid and recovering said product therefrom.

References Cited in the tile of this patent UNITED STATES PATENTS3,052,672 Nomine et al. Sept. 4, 1962

1. A COMPOUND OF THE FORMULA: